Aluminum salts of bile acids



an extensive diarrhea.

Patented Oct. 28, 1947 ALUMINUM SALTS F BILE ACIDS Clarence W. Sondern, Mendham, and Richard H. Herbine, Montville, N. J., assignors to White Laboratories, Incorporated, Newark, N. J., a corporation of New Jersey No Drawing.

2 Claims.

This invention relates to certain salts of hydroxycholanic acid, particularly to an aluminum salt thereof and to a process for obtaining such salt in a form useful as a therapeutic; agent.

Bile, as it is secreted from the gall bladder, contains certain bile salts which are essential to fat metabolism. Chemically, these bile salts comprise the taurine and glycine conjugates of certain hydroxycholanic acids, particularly cholic, desoxycholic and lithocholic acids, which acids are frequently referred to collectively as bile acids. Bile salts aid in the absorption of fats and various fat-soluble vitamins in body metabolism. When the body is deficient in such naturally occurring bile salts, it is common practice to administer certain metal salts of the bile acids in an attempt to procure the same effect as is caused by the naturally occurring substances.

Among the metal salts of the bile acids which have been used to some extent may be mentioned the strontium, iron, silver, and sodium salts. These salts have proven useful in the treatment of obstructive jaundice, in which malady both digestion and absorption of fatty substances are somewhat inhibited, and in the treatment of certain other ailments. ,However, these metal salts must often be administered in minimal dosages, which are sometimes even below an effective level, since they are relatively toxic. Many of these salts are soluble in weak acids and become active in the stomach, where they are absorbed and released into the blood stream causing a fall in blood pressure and certain other toxic symptoms. Also, the administration of previously known metal salts of the bile acids frequently leads to The need for an easily produced and effective salt of the bile acids which is not subject to the above disadvantages i evident.

It is, therefore, a principal object of this invention to provide a bile acid salt which is of therapeutic value and which is not subject to the disadvantages set forth above.

A further object of the invention is to provide a bile acid salt having a lower degree of toxicity than heretofore known metal salts of the bile acids.

An additional object of the invention is toprovide an aluminum compound of a bile acid which may be administered orally in effective doses, and which exhibits its maximum physiological activity in the alkaline regions of the intestinal tract.

Another object of this invention is to provide aluminum cholate.

An additional object of this invention is to pro Application January 5, 1946, Serial No. 639,432

Vide an aluminum bile acid salt in a therapeutically useful form.

We have prepared an aluminum compound of the bile acids, herein referred to as an aluminum bile acid salt, and determined certain characteristic properties whereby, it may be identified. The new salt is substantially insoluble in dilute acids present in the stomach and is, consequently, .well tolerated when administered orally. It is, however, soluble in dilute alkalies and decomposes in th intestinal tract to form a water-soluble bile salt which promotes complete and rapid absorption of fatty material and is otherwise valuable therapeutically. Aluminum hydroxide, formed simultaneously in the intestine with the soluble bile salt, counteracts the cathartic action and diarrhea generally caused by other metal salts of the bile acids and permits effective amounts of the aluminum bile acid salt to be administered safely.

Although the aluminum salt with which the present invention is concerned is herein referred to as an aluminum bile acid salt and may be prepared readily, as hereinafter described by the reaction of the sodium salt of'a pure bile acid with an aluminum salt, it is understood that the term applies as well to the aluminum salt obtained from the mixture of hydroxycholanic acids usually referred to as bile acids.

The new aluminum bile acid salt can be readily prepared by the interaction in aqueous solution of a soluble bile acid salt, preferably an alkalimetal salt, and a water-soluble aluminum salt, such as aluminum chloride, aluminum sulfate, aluminum nitrate, or aluminum acetate. Inorganic aluminum salts are preferably used. When aqueous solutions of water-soluble aluminum salts and of water-soluble bile acid salts aremixed, an aluminum bile acid salt is precipitated. This water-insoluble salt is recovered by filtration and may be washed or dried. Yields in excess of per cent of the theoretical amount, based on the bile acid used, can be obtained.

The preparation of the new aluminum bile acid salt. Although substantially chemically equivalent quantities of the ingredients are preferably used in the interest-of economy, considerable deviation therefrom may occur without causing undue difficulty. For best results, however, not

'small amount of insoluble impurities.

more than a small excess of free alkali should be present in the reaction mixture. Mixing of the solutions may be accomplished at ordinary room temperature, or at temperatures somewhat higher or lower. Following the mlXing of the solutions of reagents, the mixture is stirred for a short time to facilitate completion of the reaction and the precipitated aluminum bile acid salt then recovered by filtering, washing with water and drying.

Aluminum bile acid salts are white, odorless,

tasteless, amorphous substances which are only slightly soluble in alcohol, ether, water or 0.1 N hydrochloric acid. They are decomposedby-dilute alkalies with the formation of aluminum hydroxide and a. salt of the bile acid. Representative samples soften and at least partially melt unsharply at fro-m 225 to 255 C. The substances contain from about 4.5 to about 5.0 per cent of aluminum (calculated as A1203) as determined by ignition, and thus appear to contain somewhat more aluminum than might be ex-- pec'ted by considering the theoretical formulae of the salts. This may be due to the presence of a certain amount of aluminum hydroxide formed during the precipitation of the aluminum bile acid salt or it may be that a certain degree of combination of aluminum with one or more hydroxyl groups of the bile acid occurs.

The following examples illustrate the preparation of aluminum bile acid salts, but are not to be construed as limiting.

Example 1 One hundred twenty-five grams of cholic acid was dissolved in a solution of 12.5 grams of sodium hydroxide (97 per cent) in 500 milliliters of distilled water. This mixture was heated to about 85 to facilitate solution of the cholic acid. The resulting solution of sodium cholate was cooled to room temperature and filtered to remove a Twentyfive and four-tenths grams of aluminum chloride (AlClafiHzO) was then dissolved in about 3.0 liters of distilled water. The sodium cholate solution was added drop-wise tothe aluminum chloride solution over a period of about thirty minutes, the mixing being effected at room temperature. The mixture was agitated during the addition and for about one hour thereafter. The mixture was then filtered with suction, the precipitate washed free from chlorides with hot distilled water, and dried to constant weight at about 105 centigrade. One hundred sixteen and sixtenths grams of dry product was obtained. The product thus isolated was a tasteless, odorless,

amorphous, white powder, suitable for therapeutic use. It contained 4.76 per cent of aluminum (calculated as A1203) and partially melted When heate t 2 0 o 5 C,

Example 2 A solution of sodium cholate was prepared by dissolving 10.1 grams of sodium hydoxide (97 per cent) in 400 milliliters of distilled water, heating the mixture to C. and stirring into the hot solution 100 grams of cholic acid. The soluwas cooled and filtered. The pH of the sodium cholate solution was 11.5.

An aluminum chloride solution was prepared by dissolving 20.32 grams of aluminum chloride (A1C'13.6H2Q) in 400 milliliters of distilled Water. This solution had a pH of 2.9.

The sodium cholate and aluminum chloride solutions were added simultaneously and over a period of about forty-five minutes to two liters of distilled water at room temperature. The mixture was agitated during the addition and for two hours after the addition was complete. After standing for four days, the mixture was filtered with suction. The filtrate had a .pH of 3.69. The aluminum cholate was washed on. the filter until the washings no longer gave a precipitate of silver chloride with silver nitrate test solution. The aluminum cholate was then dried at C. The dry product consisted of 93.5 grams of a white, tasteless, odorless, amorphous powder. The aluminum content, as determined by washing a small sample, was 4.55 per cent, calculated as A1203. The substance softened and partially melted at 225 to 230 -C'. It had an apparent solubility in ether of 0.242 gram per hundred CLARENCE W. SONDERN. RICHARD H. .I-IERBINE.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,034,333 Doubilet Mar. 1'7, 1936 2,144,855 Rutherford Jan .24, 1939 2,306,826 Mendelsohn Dec. 29, 1942 OTHER REFERENCES Fi'eser, Chemistry of Natural Products Related to Phenanthrene, 1936, p. 126. 

